DE69812959T2 - METHOD FOR PRODUCING 2'-FLUORO-5-METHYL-BETA-L-ARABINO-FURANOSYLURIDINE - Google Patents

Description

The present invention relates to a process for the preparation of 2'-fluoro-5-methyl-β-L-arabinofuranosyluridine (more generally Name: Levovir, hereinafter referred to as "L-FMAU") represented by formula (1) what antiviral activity, particularly effective antiviral activity against hepatitis B virus (HBV) and Epstein-Barr virus (EBV) shows.

This application claims priority from the US provisional application serial no. 60 / 053,488, filed on 23. July 1997 (US 19970053488P).

Background of the Invention

worin R' eine Purin- oder Pyrimidinbase darstellt und
R'' ein Wasserstoffatom, Acyl, Alkyl, Monophosphat, Diphosphat oder Triphosphat Nucleosidverbindungen der Formel (2) zeigen antivirale Aktivität gegen HBV und EBV. Unter diesen Nucleosidverbindungen zeigt L-FMAU besonders wirksame antivirale Aktivität gegen HBV und EBV mit sehr geringer Cytotoxizität und ist deshalb als ein antivirales Mittel bevorzugt. Nucleosidverbindungen der Formel (2), einschließlich L-FMAU, sind zur Vorbeugung und Behandlung von HBV-Infektionen und verwandter Bedingungen, wie anti-HBV-Antikörper-positiver und HBV-positiver Bedingungen, chronischer, durch HBV verursachter Leberentzündung, Zirrhose, akuter Hepatitis, fulminanter Hepatitis, chronisch andauernder Hepatitis und Müdigkeit geeignet. Zusätzlich können sie ebenfalls zur Behandlung von EBV-assoziierten Erkrankungen verwendet werden.International publication WO 95/20595 and US Patent Nos. 5,587,362, 5,567,688 and 5,565,438 disclose L-FMAU and derivatives of formula (2)

wherein R 'represents a purine or pyrimidine base and
R ″ is a hydrogen atom, acyl, alkyl, monophosphate, diphosphate or triphosphate nucleoside compounds of the formula (2) show antiviral activity against HBV and EBV. Among these nucleoside compounds, L-FMAU shows particularly effective antiviral activity against HBV and EBV with very low cytotoxicity and is therefore preferred as an antiviral agent. Nucleoside compounds of formula (2), including L-FMAU, are used to prevent and treat HBV infections and related conditions such as anti-HBV antibody positive and HBV positive conditions, chronic hepatitis caused by HBV, cirrhosis, acute hepatitis , fulminant hepatitis, chronic persistent hepatitis and fatigue. In addition, they can also be used to treat EBV-associated diseases.

According to that in the international publication Methods disclosed in WO 95/20595 may include L-FMAU of formula (1) Use of L-xylose of formula (3) as a starting material getting produced.

L-xylose of formula (3) cannot from natural Substances are obtained and must therefore be synthetic Processes are made.

When L-xylose is used as the starting material production costs of L-FMAU are therefore very high.

It has now been found that L-FMAU is economical can be made from L-arabinose, which is available in many natural Substances is present and therefore represents a cheap starting material, thereby completing the present invention.

Summary the invention

It will be an improved process for the preparation of L-FMAU, which L-arabinose as the raw material used.

Short description of the figures

1 is a schematic representation of a procedure for producing L-FMAU according to the present method.

Short description the invention

Unless stated otherwise, the term alkyl refers to a saturated, straight-chain, branched-chain or cyclic, primary, secondary or tertiary hydrocarbon from C ₁ to C ₁₀ and particularly includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl. The alkyl group may optionally have one or more components selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate, either unprotected or protected if necessary be substituted, as is known to those skilled in the art, for example in Greene et al. "Protective Groups in Organic Synthesis", John Wiley and Sons, 2nd edition, 1991. The term lower alkyl as used herein refers to a C ₁ to C ₄ saturated, straight chain or branched chain alkyl group unless otherwise specified.

The term aryl used here moves unless otherwise specified, phenyl, biphenyl or naphthyl, and preferably phenyl. The aryl group may optionally have one or more units selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate, either unprotected or protected if necessary be substituted, as is known to the person skilled in the art, for example from Greene et al. "Protective Groups in Organic Synthesis", John Wiley and Sons, 2nd edition, 1991.

The term aralkyl or arylalkyl refers to an aryl group with an alkyl substituent.

The term acyl refers to a unit of the formula -C (O) R, wherein R 'is alkyl, alkoxyalkyl including methoxymethyl, arylalkyl including benzyl, aryloxyalkyl including phenoxymethyl, aryl including phenyl, optionally substituted with halogen, C ₁ to C ₄ alkyl or C ₁ to C _{4 is} alkoxy.

According to the present invention, the desired compound L-FMAU of formula (1) can be obtained economically from the starting material of formula (4) by a method using the in 1 implementation shown are produced, wherein

• a) the starting material L-arabinose of the formula (4) with a Compound of formula (18) is reacted to a compound of To obtain formula (5)
• b) the compound of formula (5) with a compound of formula (19) is condensed to obtain a compound of formula (6), which is oxidized to obtain a compound of formula (7) which then reduced to obtain a compound of formula (8)
• c) the compound of formula (8) is treated with an acid to the To obtain compound of formula (9) which with the compound of formula (18) is treated in the presence of an acid to form the compound of the formula (10) which are obtained with an acyl chloride, such as benzoyl chloride, is reacted to obtain the compound of formula (11) which then with an acid, for example acetic acid or acetic anhydride in the presence of sulfuric acid is reacted to obtain a compound of formula (12),
• d) the compound of formula (12) in the compound of formula (13) is transferred,
• e) the compound of formula (13) with a reactant to introduce a reactive leaving group is implemented around the compound of the formula (14),
• f) the compound of formula (14) is fluorinated to give the compound to obtain the formula (15), which is then subjected to halogenation to obtain the compound of formula (16), which then with a thymine base is condensed to give the compound of formula (17) and
• g) treating the compound of formula (17) with ammonia in methanol to the desired L-FMAU of formula (1).

In the above reaction scheme, R represents a hydroxy protecting group such as alkyl, aryl, haloalkyl, aralkyl, etc., R ₁ and R ₂ independently represent a hydrogen atom, alkyl or aryl, L represents a reactive leaving group such as imidazolylsulfonyl, toluenesulfonyl, Methanesulfonyl, trifluoromethanesulfonyl, etc., and Hal represents a halogen atom such as chlorine or bromine.

The method of the present invention will described in more detail below.

As in 1 is represented, by reacting the starting material, L-arabinose of the formula (4) with an alcohol of the formula (18), for example benzyl alcohol in the presence of hydrogen chloride gas, the 1-hydroxy group of the L-arabinose is protected to give the compound of the formula (5 ) to manufacture.

In reaction b), the compound of formula (5), which was prepared in reaction a), is condensed with a propane derivative of formula (19), for example 2,2-dimethoxypropane, to produce the compound of formula (6) , The compound of formula (6) is oxidized to produce the compound of formula (7), which is then reduced to produce the compound of formula (8). In this reaction, oxidizing agents which can preferably be used include aqueous chromic acid (CrO ₃ ), sodium dichromate (Na ₂ CrO ₇ ), pyridinium chlorochromate (POC), pyridinium dichromate (PDC), potassium permanganate (KMnO ₄ ), lead tetraacetate / pyridine, oxygen over platinum / Carbon catalyst, RuO ₄ , RuO ₄ / NaIO ₄ , dimethyl sulfoxide / dicyclohexylcarbodiimide (DMSO / DCC) and a proton donor, silver carbonate, triphenyl bismuth carbonate, Oppenauer oxidation (aluminum alkoxides in acetone), chlorine dioxide (ClO ₂ ), dimethyl sulfoxide / oxalyl chloride ( / (COCl) _2), dimethylsulfoxide / sulfuryl chloride (DMSO / SO ₂ Cl _2), dimethylsulfoxide / thionyl chloride (DMSO / SOCl _2), dimethylsulfoxide / toluene sulfonyl chloride (DMSO / TsCl), dimethylsulfoxide / trifluoroacetic anhydride (DMSO / (CF ₃ CO) ₂ O), dimethyl sulfoxide / acetic anhydride (DMSO / Ac ₂ O), etc. Among them, pyridinium dichromate is particularly preferred in the presence of a solvent such as dichloromethane. Reducing agents which can preferably be used include sodium borohydride (NaBH ₄ ), diisobutyl aluminum hydride (DIBAL-H), lithium borohydride (LiBH ₄ ), sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al), lithium aluminum hydride (LiA / H ₄ ), potassium borohydride (KBH ₄ ), Raney nickel, rhodium / hydrogen (H ₂ ), palladium / hydrogen, platinum / hydrogen, rubidium / hydrogen, rubidium silicon dioxide / hydrogen, etc. Among them, sodium borohydride (NaBH ₄ ) is particularly preferred.

In reaction c) the compound of formula (8) is treated with an acid such as trifluoroacetic acid delt to remove the hydroxy protecting group of the compound (8) and thereby produce the compound of the formula (9), which is then treated with the compound of the formula (18) in the presence of an acid, for example methanol in the presence of hydrochloric acid to prepare the compound of formula (10) which has a ribofuranose structure. The compound of formula (10) is then reacted with an acyl chloride such as benzoyl chloride in the presence of a base to protect all of the hydroxy groups of the compound of formula (10) with benzoyl groups and thereby produce the compound of formula (11). The compound of formula (11) is then treated with an acid such as acetic acid and acetic anhydride in the presence of sulfuric acid to produce the compound of formula (12). The series of reaction steps for the preparation of the compound of formula (12) from the compound of formula (8) can preferably be carried out sequentially, without isolating the individual intermediates.

In reaction d) the compound of formula (12), which was prepared in reaction c), with hydrogen chloride in a solvent treated like dichloromethane, cyclohexane, chloroform etc. and then with water in a solvent treated like acetonitrile to produce the compound of formula (13). In this reaction it has to Reaction by-product 1-hydroxy-isomer by treatment with ether, such as dibutyl ether, diethyl ether, etc., are removed.

In reaction e) the compound of formula (13) with a reactant to introduce a suitable reactive leaving group, for example sulfuryl chloride and imidazole, reacted to produce a compound of formula (14). This reaction can be carried out in the presence of a solvent such as dimethylformamide. Dichloromethane, etc. become.

In reaction f), the compound of formula (14) prepared in reaction e) is fluorinated in the presence of a solvent such as ethyl acetate, whereby the reactive leaving group is substituted with fluorine to produce a compound of formula (15). In this reaction the preferred fluorinating agent includes potassium hydrogen fluoride (KHF ₂ ) / hydrofluoric acid / pyridine or hydrofluoric acid / amine such as triethylamine. The resulting compound of formula (15) is then halogenated, for example with hydrobromic acid or hydrochloric acid in the presence of acetic acid, to produce the compound of formula (16). The compound of formula (16) is then reacted with a thymine base in the presence of hexamethyldisilazane and ammonium sulfate to produce a compound of formula (17). This reaction can preferably be carried out in the presence of a solvent, for example chloroform, dichloromethane, 1,2-dichloroethane, acetonitrile, etc.

In reaction g) the compound of formula (17), which was prepared in reaction f) with Treated ammonia in the presence of a solvent the benzoyl group, i.e. the hydroxy protecting group, from the compound of formula (17) and thereby produce the desired compound L-FMAU.

Although numerous aspects of the present invention The present is illustrated by the following examples The invention is in no way limited to these examples. Other Reactants such as those known to those of ordinary skill in the art can be used which have essentially the same function. In the number of the connections in brackets corresponds to the examples the number in reaction scheme A.

Example 1: Production of 1-O-benzene-α-L-arabinoside (5)

1000 ml of benzyl alcohol is saturated with hydrogen chloride for 40 minutes at 0 ° C, 200 g (1.33 mol) of L-arabinose is added and the resulting mixture is stirred at room temperature for 10 hours, during which a lot of compound (5) precipitates , To induce additional precipitation, 1.51 ethyl acetate is slowly added while the mixture is stirred. The resulting solid product is filtered, washed with ethyl acetate and then air-dried, whereby 300 g (yield: 94%) of the title compound (5) are obtained in the form of a white solid.
Melting point: 170-171 ° C
¹ H NMR δ (ppm): 3.46 (q, 1 H, J = 2.87, 11.8), 3.63-3.73 (m, 4H), 4.45 (d 1 H, J = 12.8), 4.76 (d, 1 N, J = 12.32), 7.29-7.38 (m, 5H)

Example 2: Production of 1-O-benzene-3,4-O-isopropylidene-R-L-riboside (8)

A mixture of 200 g (0.83 mol) of 1-O-benzyl-β-L-arabinoside (5), 240 ml (1.95 mol) of 2,2-dimethoxypropane and 4 g (0.02 mol) of p- TsOH H ₂ O in 2000 ml acetone is stirred at room temperature for 2 hours. The reaction mixture thus obtained is neutralized with triethylamine and evaporated under reduced pressure, after which the compound of formula (6) is obtained in the form of a yellowish syrup, which is used in the next reaction without further purification.

To a mixture of compound (6) and 240 g (0.63 mol) of pyridinium dichromate in 2000 ml of dichloromethane is added 240 ml (2.54 mol) of acetic anhydride at 0 ° C and the resulting mixture is then refluxed until the starting material has disappeared (approx. 4 hours). At this point the system is ventilated. The solvent is removed under reduced pressure until the mixture occupies one third of its initial volume, and the residue is dissolved in 1500 ml of ethyl acetate with vigorous stirring, which is determined using a me chanian stirrer is poured into it. The resulting mixture is filtered through a pad of Celite and the filter cake is washed carefully with ethyl acetate. The blackish, combined filtrate is filtered through a silica gel (2-20 micrometer) column (20 cm high, 10 cm diameter). The silica gel is washed with ethyl acetate until compound (7) can no longer be detected by TLC. The clear, combined filtrate thus obtained is evaporated, after which the compound (7) is obtained in the form of a syrup, which is evaporated twice with toluene.

The purified syrup (7) thus obtained is dissolved in 2000 ml of methanol and cooled to -20 ° C. 40 g (1.06 mol) of NaBH ₄ pellets are added very slowly to the resulting solution over 3 hours at -20 ° C. After the reaction is complete, the solution is neutralized with acetic acid and evaporated under reduced pressure, after which a white, solid residue is obtained. The residue is partitioned between 1000 ml of ethyl acetate and 200 ml of water. The aqueous layer is extracted with 100 ml of ethyl acetate. The combined organic layer is washed with 200 ml of brine, dried over MgSO ₄ and then evaporated to give a white solid, which is recrystallized from 700 ml of hot hexane, after which 123 g (yield: 53% from the compound (5) ) of compound (8) can be obtained in the form of white crystals.
Melting point: 79-80 ° C [a] ²⁵ _D = + 143 ° (c 0.7, ethanol)
¹ H NMR δ (ppm): 1.37 (s, 3H), 1.55 (s, 3H), 2.37 (d, 1H, J = 6.45), 3.71-3.76 (m , 2H), 3.86 (q, 1N, J = 3.44 and 12.89), 4.27-4.30 (m, 1H), 4.49-4.52 (m, 1N ), 4.56 (d, 1 H, J = 11.8), 4.83 (d, 1 N, J = 11.8), 4.86 (d, 1 H, J = 5.40), 7.26-7.36 (m, 5H)

Example 3: Production of 1-O-acetyl-2,3,5-tri-O-benzoyl-R-L-ribofuranose (12)

201 g (0.717 mol) of the compound (8) dissolved in 1000 ml of 4% trifluoroacetic acid (CF ₃ COOH) is refluxed until the starting material (approx. 1 hour) and the intermediate (1-O-benzyl derivative) have disappeared (approx. 4-8 hours). The reaction mixture is cooled to room temperature and then washed with dichloromethane (4 × 500 ml) to remove benzyl alcohol. The aqueous layer thus obtained is evaporated under vacuum and coevaporated with toluene (2 × 200 ml), after which the compound (9) is obtained in the form of a yellowish syrup which is dried completely under high vacuum to remove a trace amount of water.

Compound (9) is dissolved in 2000 ml of methanol and 15.8 g (0.43 mol) of HCl (gas) is introduced into the mixture at room temperature. The mixture thus obtained is stirred at room temperature for 2 hours, neutralized with 183 ml of pyridine and concentrated in vacuo at 30 to 35 ° C, after which a yellowish syrup is obtained, which is then evaporated together with pyridine, after which the compound (10) in in the form of a yellowish syrup. Compound (10) is dissolved in 800 ml of pyridine and 212 ml of benzoyl chloride is added dropwise to the mixture at 0 ° C. The mixture is stirred at room temperature for 8 hours. After the reaction has largely ended, the mixture is heated to 45 ° C. for 1.5 hours. The mixture is cooled to room temperature and ice is added to remove the remaining benzoyl chloride. Pyridine is evaporated from the mixture at 35 to 40 ° C until the mixture obtained has half of its initial volume. The residue is dissolved in 1500 ml of ethyl acetate, which is then washed with 500 ml of cold water, 576 ml of cold 3N H ₂ SO ₄ , 500 ml of aqueous sodium bicarbonate (x 2) and 500 ml of alkali in this order. The organic layer is dried over MgSO ₄ and activated carbon, filtered through a pad of silica gel (2-20 μ) and evaporated, after which compound (11) is obtained in the form of a yellowish syrup.

To a mixture of the compound (11) dissolved in 144 ml (2.52 mol) of acetic acid and 334 ml (3.54 mol) of acetic anhydride is slowly added 48 ml (0.9 mol) of conc. H ₂ SO _{4 added} dropwise at 0 ° C during which crystallization occurs. The mixture is brought to room temperature and stored in a refrigerator overnight. The mixture is poured into 700 ml of an ice water mixture, filtered and the filter cake is washed twice with cold water. The solid is dissolved in 2000 ml of ethyl acetate, which is then washed with 500 ml of water, 500 ml of saturated sodium bicarbonate and 500 ml of alkali. The organic layer is dried over MgSO ₄ and activated carbon and the resulting mixture is filtered through a silica gel pad (2-20 μ). The solvent is removed and the residue is recrystallized from methanol to give 144.7 g (yield: 40% of Compound (8)) of Compound (12) as a white solid.
Melting point: 124-125 ° C [a] ²⁵ _D = –22.1 ° (c 1, pyridine)
¹ H NMR (CDCl ₃ ) δ (ppm): 8.90-7.32 (m, 15H, Ar-H), 6.43 (s, 1H, H-1), 5.91 (dd, 1H, H-3, J = 4), 5.79 (d, 1H, H-2, J = 8), 4.81-4.76 (m, 2H, H-4 and H-5), 4.54 -4.49 (m, 1 H, H-5), 2.00 (s, 3H, CH ₃ COO)

Example 4: Production of 1,3,5-tri-O-benzoyl-α-L-ribofuranose (13)

HCl (gas) is passed for 1.5 hours into a solution of 50 g (99.16 mol) of the compound (12) dissolved in 460 ml of anhydrous dichloromethane and 7.5 ml of acetyl chloride at 0 ° C. The resulting solution is kept in a refrigerator for 12 hours and then evaporated under vacuum. The The residue is evaporated together with toluene (3 × 150 ml) at 45 ° C. and redissolved in 105 ml of acetonitrile. 13 ml of water are added dropwise to this solution at 0.degree. A white solid begins to precipitate out of the mixture after 30 minutes after keeping the mixture in a refrigerator for 2 hours to induce additional precipitation. After filtering the resulting solid, the filter cake is washed carefully with cold diethyl ether to remove the reaction by-product 1-hydroxy isomer, which cannot be distinguished from compound (13) by TLC. The white solid thus obtained is dissolved in ethyl acetate. The solution is washed with saturated sodium bicarbonate to remove the remaining HCl, dried over MgSO ₄ and filtered. The solvent is removed from the filtrate to give 29.2 g (yield: 63.7%) of compound (13) in the form of a white solid.
Melting point: 137-139 ° C [a] ²⁵ _D = -82.01 ° (c 1.5, CHCl ₃ )
¹ H NMR (CDCl ₃ ) δ (ppm): 7.31, 8.19 (m, 15H, Ar-H), 6.69 (d, J = 4.6 Hz, 1H, H-1), 5 , 59 (dd, J = 6.7, 1.8 Hz, 1H, H-3), 4.64, 4.80 (m, 4H, H-2, H-4 and H-5), 2, 30 (br s, D ₂ O interchangeable, OH)

Example 5: Production of 1,3,5-tri-O-benzoyl-2-O-imidazylolsulfonyl-α-L-ribofuranose (14)

107.0 g (0.232 mol) of compound (13) is dissolved in 1070 ml of dichloromethane and 214 ml of dimethylformamide, to which 62.5 g (37.2 ml, 0.463 mol) of sulfuryl chloride are added dropwise at a low temperature (-10 to -78 ° C) is added. The resulting solution is stirred at room temperature for 3 hours and then cooled in an ice bath. The solution is stirred while 157.8 g (2.32 mol) of imidazole is added portionwise at a rate which keeps the temperature of the reaction mixture below 5 ° C. The resulting mixture is stirred for 20 hours at room temperature, after which 400 ml of ice water is added. The aqueous layer is extracted three times with 100 ml dichloromethane (3 x 100 ml). The combined organic solution is washed with 200 ml of alkali and dried over MgSO ₄ . The solvent is removed under reduced pressure and dimethylformamide is removed under high vacuum. The syrup-like residue is evaporated together with 100 ml of 2-propanol under reduced pressure, after which a white solid (14) is obtained, which is used in the subsequent reaction without further purification.

Example 6: Production of 1- (3,5-di-O-benzoyl-2-fluoro-β-L-arabinofuranosyl) thymine (17)

A mixture of the imidazolate (14) obtained in Example 5, 224.1 g (1.39 mol) of triethylamine-3HF and 824 ml of ethyl acetate is heated to 80 ° C. for three hours and then 70.3 g (92.5 ml , 0.696 mol) of triethylamine are slowly added and the mixture thus obtained is stirred for a further hour at the same temperature, after which the mixture is cooled to room temperature. The resulting solution is poured into ice water containing NaHCO ₃ to neutralize it to pH 7. The aqueous layer is extracted three times with 100 ml of ethyl acetate (3 × 100 ml). The combined organic solution is washed with brine and dried over Na ₂ SO ₄ . The solvent is removed and the residue is redissolved in 300 ml of dichloromethane. The solvent is removed to give 101.0 g of crude 2-fluoro-sugar product (15) which is redissolved in 150 ml of dichloromethane. 195.9 ml (88.2 g, 1.09 mol) of hydrobromic acid / acetic acid (45% w / v) is added to the solution at 0 ° C. and then stirred at room temperature for 15 hours. The resulting solution is evaporated to dryness under reduced pressure to give a syrup which is coevaporated with toluene (3 x 100 ml) and a sugar bromide (16) is obtained in the form of a semi-solid material which is then obtained in 200 ml of chloroform is dissolved again for the condensation reaction described below.

A mixture of 55.44 g (0.44 mol) of thymine, 5 g of ammonium sulfate ((NH ₄ ) ₂ SO ₄ ) and 212.5 g (278.9 ml, 1.32 mol) of hexamethyldisilazane in 1900 ml of chloroform is used for Refluxes for 24 hours, after which an approximately clear solution is obtained. A solution of the sugar bromide (16) in chloroform is added and the resulting mixture is refluxed for a further 24 hours and then cooled to room temperature. 200 ml of water is added to the reaction mixture, which is stirred at room temperature for 30 minutes and then filtered. The organic layer is separated, dried over Na ₂ SO ₄ and filtered through a pad of Celite, which is then washed with ethyl acetate. The combined organic solution is evaporated to give a solid which is recrystallized from 100 ml of ethanol, after which 78.0 g (yield: 69.5 g of the alcohol compound (13)) 3,5-O-dibenzoyl-L- FMAU (17) can be obtained in the form of crystals.
Melting point: 118-120 ° C [a] ²⁰ _D = + 22.40 ° (c 0.31, CHCl ₃ ) UV (MeOH) λ _max 264.0 nm
¹ H NMR (CDCl ₃ ) δ (ppm): 8.55 (s, NH) 7.37, 8.12 (m, Ar), 6.35 (dd, J _F _ _H = 22.4 Hz, N -1 '), 5.64 (dd, J _F _ _H = 20.4 Hz, H-3'), 5.32 (dd, J _F _ _H = 50.2 Hz, H-2 '), 4 , 82 (m, H-5), 4.50 (m, H-4 '), 1.76 (s, CH ₃ )

Example 7: Production of 2'-fluoro-5-methyl-β-L-arabinofuranosyluridine (1)

NH ₃ gas is introduced for 2-3 hours into a suspension of 83.0 g (0.18 mol) of compound (17) in 1000 ml of methanol, after which a clear solution is obtained, which is then at room temperature is stirred for a further 48 hours. The solvent is removed under reduced pressure and the residue is triturated with diethyl ether. The resulting solid is collected by filtration, redissolved in 500 ml of methanol and decolorized twice with coal.

Methanol is removed and the resulting solution is refluxed with 200 ml of acetonitrile for 2 hours. The resulting mixture is refrigerated for 15 hours and then filtered to obtain 35.6 g (yield: 77.35%) of a white solid. The mother liquor is concentrated to dryness and purified by silica gel chromatography (1-10% methanol in chloroform) to give a white solid which is refluxed with 20 ml of acetonitrile, after which 4.98 g (yield: 10.8% ) of the second crop of the product. The overall yield is increased to 88.2% (40.58 g).
Melting point: 185-187 ° C [a] ²⁰ _D = -112.06 ° (c 0.23, methanol)
UV (H ₂ 0) λ _max 265.0 (ε 9695) (pH 2), 265.5 (ε 9647) (pH 7), 265.5 nm (ε 7153) (pH 11)
¹ H NMR (DMSO-d) δ (ppm): 11.45 (s, NH), 7.59 (s, H-6), 6.10 (dd, J _F _ _H = 15.4 Hz, N -1 '), 5.88 (d, 3'-OH), 5.12 (t, 5'-OH), 5.04 (dt, J _F _ _H = 52.8 Hz, H-2') , 4.22 (dq, J _F _ _H = 18.4 Hz, H-3 '), 3.76 (m, H-4'), 3.63 (m, H-5 '), 1.78 (s, CH ₃ )

Claims (14)

Process for the preparation of 2'-fluoro-5-methyl-β-L-arabinofuranosyluridine (L-FMAU) of the formula (1)

which the use of L-arabinose of the formula (4)

as a starting material. The method of claim 1, wherein a) L-arabinose of formula (4) with a compound of formula (18) R-OH (18) is reacted to give a compound of formula (5)

to obtain in which R represents a hydroxy protecting group, b) the compound of formula (5) with a compound of formula (19) H ₃ CO-C (R ₁ R ₂ ) -OCH ₃ (19) is condensed to a compound of formula (6)

to obtain the compound of formula (6) is oxidized to give a compound of formula (7)

to obtain the compound of formula (7) is then reduced to a compound of formula (8)

to obtain wherein R ₁ and R ₂ independently represent a hydrogen atom, alkyl or aryl and R represents a hydroxy protecting group, c) the compound of formula (8) is treated with an acid to give a compound of formula (9)

to obtain the compound of formula (9) with a compound of formula (18) R-OH (18) treated in the presence of an acid to give a compound of formula (10)

and the compound of formula (10) is reacted with benzoyl chloride to give a compound of formula (11)

to obtain which is then reacted with acetic acid and acetic anhydride in the presence of sulfuric acid to give a compound of formula (12)

to obtain wherein R is a hydroxy protecting group, d) the compound of formula (12) into a compound of formula (13)

is converted, e) a reactive leaving group is introduced into the compound of the formula (13) to give a compound of the formula (14)

to obtain wherein L represents a reactive leaving group, f) the compound of formula (14) is fluorinated to give a compound of formula (15)

the compound (15) is subjected to halogenation to give a compound of the formula (16)

and the compound of the formula (16) is condensed with thymine base to give a compound of the formula (17)

where Hal is a halogen atom, and g) treating the compound of formula (17) with ammonia in methanol to produce the desired L-FMAU of formula (1). The method of claim 1 which includes the step of protecting the hydroxy group in the 1-position of the L-arabinose of formula (4)

by reaction with a compound of formula (18) R-OH (18) wherein R is benzyl, aryl or aralkyl to give a compound of formula (5)

and then converting the compound of formula (5) into an L-ribose of formula (10)

includes. The method of claim 1, further comprising the step of condensing a compound of formula (5)

with a compound of formula (19) H ₃ CO-C (R ₁ R ₂ ) -OCH ₃ (19) a compound of formula (6)

to oxidize the compound of formula (6) to give a compound of formula (7)

and reducing the compound of formula (7) to give a compound of formula (8)

to obtain, wherein R ₁ and R ₂ independently represent a hydrogen atom, alkyl or aryl. The method of claim 4, further comprising the step of treating the compound of formula (8) with an acid to give a compound of formula (9)

to treat the compound of formula (9) with a compound of formula (18) R-OH (18) in the presence of an acid to give a compound of formula (10)

to react the compound of formula (10) with benzoyl chloride to obtain a compound of formula (11)

to react the compound of formula (11) with acetic acid and acetic anhydride in the presence of sulfuric acid to give a compound of formula (12)

to get included. The method of claim 5, further comprising the step of converting the compound of formula (12) into a compound of formula (13)

and introducing a reactive leaving group into the compound of formula (13) to give a compound of formula (14)

to obtain, wherein L represents a reactive leaving group. The method of claim 6, further comprising the step of fluorinating the compound of formula (14) to a compound of formula (15)

halogenating the compound of the formula (15) to give a compound of the formula (16)

and condensing the compound of formula (16) with thymine base to give a compound of formula (17)

to obtain, wherein Hal represents a halogen atom. The method of claim 7, further comprising the step of treating the compound of formula (17) with ammonia in methanol to give the desired L-FMAU of formula (1). A method according to claim 2 or claim 4, wherein the oxidation of the compound of formula (6) to obtain the compound of formula (7) using aqueous chromic acid, sodium dichromate, pyridinium chlorochromate, pyridinium dichromate, potassium permanganate, lead tetraacetate / pyridine, oxygen over platinum / carbon -Catalyst, RuO ₄ , RuO ₄ / NaIO ₄ , dimethyl sulfoxide / dicyclohexylcarbodiimide and a proton donor, silver carbonate, triphenyl bismuth carbonate, Oppenauer oxidation (aluminum alkoxides in acetone), chlorine dioxide, dimethyl sulfoxide / oxalyl chloride, dimethyl sulfoxide / sulfuryl chloride / dimethyl sulfonyl chloride, dimethyl sulfonyl chloride, dimethyl sulfonyl chloride, Dimethyl sulfoxide / trifluoroacetic anhydride or dimethyl sulfoxide / acetic anhydride is carried out. The method of claim 2 or claim 4, wherein the reduction the compound of the formula (7) to obtain the compound of the formula (8) using sodium borohydride, diisobutyl aluminum hydride, Lithium borohydride, sodium bis (2-methoxyethoxyaluminium hydride, lithium aluminum hydride, potassium borohydride, Raney nickel, rhodium / hydrogen, palladium / hydrogen, platinum / hydrogen, Rubidium / hydrogen or rubidium silicon dioxide / hydrogen is carried out. A method according to claim 2 or claim 6, wherein in the transfer the Compound of formula (12) into the compound of formula (13) that Reaction by-product 1-hydroxy isomer using diethyl ether or dibutyl ether is removed. Method according to one of claims 2, 6 or 7, wherein L is a Is imidazolylsulfonyl group. The method of claim 2 or claim 6, wherein introducing a reactive leaving group in the compound of formula (13) to obtain the compound of formula (14) using imidazole and Sulfonyl chloride performed is an imidazolylsulfonyl group as the reactive leaving group introduce. The method of claim 2 or claim 7, wherein the fluorination the compound of the formula (14) to obtain the compound of the formula (15) using potassium hydrogen fluoride / hydrofluoric acid / pyridine or hydrofluoric acid / triethylamine carried out becomes.